Promise of SGLT2 Inhibitors in Heart Failure: Diabetes and Beyond
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This review provides mechanistic insight in the pleiotropic effects of sodium-glucose transporter-2 (SGLT-2) inhibitors with particular interest to the pathophysiology of heart failure. The SGLT-2 inhibitor empagliflozin has recently demonstrated an unprecedented 38% reduction in cardiovascular mortality in patients with diabetes. Despite modest effects on long-term glycemic control, highly significant reductions in heart failure admissions and end-stage kidney disease were observed. SGLT-2 inhibitors are the latest approved class of glucose-lowering agents. By blocking sodium/glucose uptake in the proximal tubules of the nephron, they induce glycosuria. Treatment with SGLT-2 inhibitors in diabetes leads to a sustained ∼1% reduction in glycated hemoglobin levels, with favorable reductions in both arterial blood pressure (∼3–6 mmHg) and body weight (∼2–4 kg/m2). However, those effects fail to explain fully the dramatic reduction in cardiovascular mortality, heart failure readmissions, and end-stage kidney disease. The unique pharmacological profile of SGLT-2 inhibitors puts them at the crossroads of important hemodynamic, neurohumoral, metabolic, and vascular endothelial pathways influencing cardiac and renal disease. SGLT-2 inhibitors decrease proximal tubular sodium and chloride reabsorption, leading to a reset of the tubuloglomerular feedback. This induces plasma volume contraction without activation of the sympathetic nerve system, decreases harmful glomerular hyper-filtration leading to better long-term renal preservation, and improves diuretic and natriuretic responses to other diuretic agents. Moreover, SGLT-2 inhibitors might improve the efficiency of myocardial energetics by offering β-hydroxybutyrate as an attractive fuel for oxidation and increase hematocrit improving oxygen transport. Finally, decreased vascular stiffness and improved endothelial function are observed with the use of SGLT-2 inhibitors in diabetes. Those multiple nonglycemic effects reinforce SGLT-2 inhibitors as the preferred glucose-lowering drug to treat diabetic patients with heart failure. In the future, they might even be considered in heart failure or chronic kidney disease patients without diabetes.
KeywordsDiabetes mellitus Energy metabolism Glomerular filtration rate Heart failure Plasma volume Sodium-glucose transporter 2
Compliance with Ethical Standards
Conflict of Interest
Pieter Martens is supported by a doctoral fellowship by the Research Foundation – Flanders (FWO, 1127917N) and is a researcher for the Limburg Clinical Research Program (LCRP) UHasselt-ZOL-Jessa, supported by the foundation Limburg Sterk Merk (LSM), Hasselt University, Ziekenhuis Oost-Limburg and Jessa Hospital.
Chantal Mathieu and Frederik H. Verbrugge each declare no potential conflicts of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
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